Tacrolimus, a member of macrolides immunosuppressant, chemical name 17-aryl-1,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylbinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo [22.3.1.04, 9] octacos-18-en-2,3,10,16-tetraone has been isolated from culture of Streptomyces tsukubaensis, and its monohydrate form represented by the following formula:
has been commonly used as a pharmaceutical. It has been known that tacrolimus has advantageous pharmacological effects including immunosuppressant effect and antimicrobial effect, and that it is thus useful for the treatment and prevention of various autoimmune diseases such as organ or tissue transplant rejection or graft vs host disease, infection diseases and the like (see Patent Reference 1).
It has also been known that external application of tacrolimus is useful for the treatment of cutaneous diseases such as atopic dermatitis (Patent Reference 2). There has been a significant increase in the number of patients suffering from atopic dermatitis recently. It has been known that skin of a patient suffering from atopic dermatitis has lower contents of epidermal lipid and keratoid moisture, lesser ability to form hydrolipidic film, and lower resistance threshold against external irritations comparing to those of normal subjects. Furthermore, it has also been known that abnormal-dryness or pruritus of skin results from a wreck of barrier function of skin. Therefore, there is a need for an external preparation comprising tacrolimus.
Since tacrolimus dissolves poorly in water and lipid solvent, a preparation comprising it requires solubilizers capable of solubilizing tacrolimus. Typically surfactants are used as the solubilizer. However, surfactants are not suitable for a preparation for treating cutaneous diseases such as atopic dermatitis because of its dermal irritation. Useful solubilizers other than surfactants are very limited. Such solubilizers may have dermal irritation like as surfactants or may chemically destabilize an active ingredient such as tacrolimus, it is thus unfavorable to use solubilizers having said undesired properties. In addition, for the purpose of decreasing dermal irritation caused by tacrolimus ointment, preferred is solubilizers capable of forming stable droplet dispersion which do not misce with ointment base. Moreover, in the case of the treatment of cutaneous diseases such as atopic dermatitis, preferred is topical delivery of tacrolimus because the drug is an immunosuppressant. If tacrolimus is administered systemically, undesired side effects such as dysfunction of kidney and a risk to be affected with diseases which must be normally prevented by an immune system would be caused. Furthermore, preferred is having sufficient chemical and physical stability for a pharmaceutical product.
There has been tacrolimus containing external preparations, for example ointment (see Patent Reference 3), lotion (see Patent Reference 4), cream (see Patent Reference 5) and gel (see Patent Reference 6). However there are technical problems in those preparations that the preparation comprises agents having high dermal irritation or that the active ingredient tacrolimus is decomposed during long-term storage. Therefore, there is still a need for a tacrolimus containing external preparation having low dermal irritation and excellent stability. For example, there has been marketed a tacrolimus ointment as the trade name Protopic® ointment, which comprises propylene carbonate. However propylene carbonate has dermal irritation, it is thus not suitable for na ointment.    Patent Reference 1: JP-A-61-148181    Patent Reference 2: JP-A-1-157913    Patent Reference 3: JP-A-5-17481    Patent Reference 4: WO94/028894    Patent Reference 5: JP-A-2000-513739    Patent Reference 6: WO99/055332